Variant 3-183015560-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020166.5(MCCC1):c.2056A>G(p.Ile686Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MCCC1
NM_020166.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.49

Variant links:

Genes affected

MCCC1 (HGNC:6936): (methylcrotonyl-CoA carboxylase subunit 1) This gene encodes the large subunit of 3-methylcrotonyl-CoA carboxylase. This enzyme functions as a heterodimer and catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA. Mutations in this gene are associated with 3-Methylcrotonylglycinuria, an autosomal recessive disorder of leucine catabolism. [provided by RefSeq, Jul 2008]

MCCC1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20959347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCCC1	NM_020166.5 linkuse as main transcript	c.2056A>G	p.Ile686Val	missense_variant	19/19	ENST00000265594.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCCC1	ENST00000265594.9 linkuse as main transcript	c.2056A>G	p.Ile686Val	missense_variant	19/19	1	NM_020166.5	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249128

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 17, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 27, 2021	This sequence change replaces isoleucine with valine at codon 686 of the MCCC1 protein (p.Ile686Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs751755306, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with MCCC1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.2

L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.64

N;N;.

REVEL

Benign

0.22

Sift

Benign

0.12

T;T;.

Sift4G

Benign

0.21

T;T;T

Polyphen

0.84

P;D;.

Vest4

0.13

MutPred

0.67

Gain of methylation at K687 (P = 0.066);.;.;

MVP

0.31

MPC

0.22

ClinPred

0.41

GERP RS

3.3

Varity_R

0.067

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over